This invention relates to the preparation of fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, which is also known as sevoflurane.
Sevoflurane is an inhalation anesthetic agent, first disclosed in U.S. Pat. Nos. 3,476,860 and 3,689,571. Sevoflurane exhibits rapid induction and recovery compared to halothane. Although unstable to soda lime, sevoflurane may have use in countries such as Japan which do not employ a closed breathing circuit comprising soda lime.
Several methods have been disclosed for preparing sevoflurane. For example, according to Regan et al., U.S. Pat. No. 3,689,571, sevoflurane may be made by photochemical chlorination of methyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, of which the preparation is disclosed in U.S. Pat. No. 3,346,448, to produce chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, followed by a substitution reaction with potassium fluoride in solvent. Alternatively, sevoflurane may be made by fluorination of methyl 1,1,1,3,3,3-hexafluoro-2-propyl ether with bromine trifluoride, or by the combined reaction of 1,1,1,3,3,3-hexafluoro-2-propanol, paraformaldehyde and anhydrous hydrogen fluoride followed by heating the product with excess anhydrous hydrogen fluoride. A method involving the reaction of methyl 1,1,1,3,3,3-hexafluoro-2-propyl ether and bromine trifluoride is also disclosed in Zh. Obshch. Khim., vol. 37, pp. 375-380 (1967) and Chem. Abstracts, vol. 67, No. 43357x. Another method, which represents an improved reaction of 1,1,1,3,3,3-hexafluoro-2-propanol, paraformaldehyde and hydrogen fluoride, is disclosed in U.S. Pat. No. 4,250,334, which discloses using concentrated sulfuric acid and continuously collecting product vapors in a cold collector. This continuous method is improved further as disclosed in U.S. Pat. No. 4,469,898, which discloses adding 1,1,1,3,3,3-hexafluoro-2-propanol to a preformed mixture of formaldehyde, hydrogen fluoride and a dehydrating, protonating and fluoride ion generating agent. Another method for preparing fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether is disclosed in U.S. Pat. No. 3,897,502. In this method, methyl 1,1,1,3,3,3-hexafluoro-2-propyl ether is reacted with fluorine in argon and Freon E-3 to produce sevoflurane.
The methods mentioned above involve the use of relatively expensive starting materials, notably 1,1,1,3,3,3-hexafluoro-2-propanol or the very toxic hexafluoroacetone. The manufacturing cost of the final product is therefore commensurately higher.
It has been known that bromine trifluoride is able to replace a halogen atom, other than fluorine, by a fluorine atom. For example, A. A. Banks et al., in J. Chem. Soc., 2188 (1948), disclose the reaction of bromine trifluoride and carbon tetrahalide (except fluoride) to produce carbon monofluoro and carbon difluoro-halides. Similar reactions are disclosed by R. A. Davis et al. in J. Org. Chem., 32, 3478 (1967) in which up to two bromine atoms in bromofluoroethanes are displaced by reactions with bromine trifluoride. B. M. Regan et al., as disclosed in U.S. Pat. Nos. 3,689,459, 3,773,840 and 3,976,788, used bromine trifluoride to replace one or two chlorine atoms with fluorine at the .alpha.-carbon of ethers to make fluorinated ethers.
Applicants have now discovered a unique method for mono-hydrogen and poly-chlorine displacements, especially at the .beta.-carbon to the oxygen, at the same time in either methyl or chloromethyl 1,1,1,3,3,3-hexa-chloro-2-propyl ether using a halogen fluoride such as bromine trifluoride as a multi-substituting and fluorinating agent to produce sevoflurane in as short as one step.